1. Field of the Invention
The present invention relates to pyridone derivatives or salts thereof, or crystals thereof, which have Axl inhibitory activity.
2. Description of the Related Art
Axl is a receptor tyrosine kinase of the Tyro3-Axl-Mer (TAM) receptor tyrosine kinase family, which has the growth arrest-specific gene 6 (Gas6) protein as a ligand. Axl has initially been identified as a transforming gene in chronic myelogenous leukemia (O'Bryan et al., Mol. Cell. Biol., 1991, 11, 5031).
The Gas6/Axl signaling pathway has been reported to modulate various cellular responses such as cell survival, cell division, autophagy, cell migration, angiogenesis, platelet aggregation and NK cell differentiation (Rachel M A Linger et al., Expert Opin. Ther. Targets, 2010, 14, 1073). Axl also has often been reported to be overexpressed in cancer tissues such as tissues of primary colon cancer (Craven et al., Int. J. Cancer., 1995, 60, 791), gastric cancer (Sawabu et al., Mol. Carcinog., 2007, 46, 155), esophageal cancer (Nemoto et al., Pathobiology, 1997, 65, 195), melanoma (Quong et al., Melanoma Res., 1994, 4, 313), ovarian cancer (Sun et al., Oncology, 2004, 66, 450), renal cancer (Chung et al., DNA Cell Biol., 2003, 22, 533), endometrial cancer (Sun et al., Ann. Oncol., 2003, 14, 898) and thyroid cancer (Ito et al., Thyroid, 1999, 9, 563). It has also been demonstrated that the presence of Axl is greatly related to the lymph node status and the stage in lung cancer, and the ER expression in breast cancer (Berclaz et al., Ann. Oncol., 2001, 12, 819).
It has further been demonstrated that Axl has a role in immunity (Lu et al., Science, 2001, 293, 306), platelet function (Angelillo-Scherrer et al., Nat. Med., 2001, 7, 215), spermatogenesis (Lu et al., Nature, 1999, 398, 723), vascular calcification (Son et al., Eur. J. Pharmacol., 2007, 556, 1), thrombin-induced vascular smooth muscle cell (VSMC) growth (Nakano et al., J. Biol. Chem., 1995, 270, 5702), and various renal diseases such as acute and chronic glomerulonephritis, diabetic nephropathy and chronic allograft rejection (Yanagita et al., J. Clin. Invest., 2002, 110, 239). Axl inhibitors are expected to be useful not only for the treatment of cancer (including solid tumors such as carcinoma and sarcoma, leukemia, and lymphoid malignancy) but also for the treatment of many diseases such as vascular diseases (including, but not limited to, thrombosis, atherosclerosis and restenosis), renal diseases (including, but not limited to, acute and chronic glomerulonephritis, diabetic nephropathy, and transplant rejection), and diseases with significant chaotic angiogenesis (including, but not limited to, diabetic retinopathy, retinopathy, psoriasis, rheumatoid arthritis, atheroma, Kaposi's sarcoma and hemangioma).
Compounds reported to inhibit Axl include compounds having a sulfonamide structure (WO 2008/128072), compounds having a pyrrolopyrimidine structure (US Patent Application Publication No. 20100204221 and WO 2010/090764), compounds having pyridine and pyrazine structures (WO 2009/053737), compounds having a pyrazine structure (WO 2009/007390), compounds having a pyrazinylbenzimidazole structure (WO 2009/024825), compounds having an indolinone structure (WO 2007/057399), compounds having triazolopyridine and triazolopyrimidine structures (WO 2009/047514), compounds having an imidazole structure (WO 2009/058801), compounds having a triazole structure (WO 2008/083367, WO 2008/083353, WO 2010/005879, WO 2008/083357, WO 2008/083356, WO 2008/083354, WO 2007/030680, WO 2009/054864, WO 2010/005876, WO 2009/054864, US Patent Application Publication No. 20090111816 and US Patent Application Publication No. 20100168416), compounds having a pyrimidinediamine structure (WO 2008/045978), compounds having a pyrimidine structure (WO 2007/070872, Alexis Mollard et al., Med. Chem. Lett., 2011, 2, 907 and D Mahadevan et al., Oncogene, 2007, 26, 3909), compounds having a quinolinyloxyphenylsulfonamide structure (WO 2011/045084), compounds having a quinoline structure (WO 2009/127417, US Patent Application Publication No. 20090274693 and Yi-Xiang Zhang et al., Cancer Res., 2008, 68, 1905), compounds having a pyridine structure (WO 2007/066187 and Gretchen M. Schroeder et al., J. Med. Chem., 2009, 52, 1251), compounds having a urea structure (WO 2009/138799), compounds having a 2,4-disubstituted arylamide structure (Carl R. Illig et al., Bioorg. Med. Chem. Lett., 2008, 18, 1642), compounds having a secosteroid structure (Daowan Lai et al., Bioorg. Med. Chem., 2011, 19, 6873), compounds having a bicyclic pyrimidine structure (US Patent Application Publication No. 20100069369 and US Patent Application Publication No. 20070142402) and compounds having aminopyrazine and aminopyridine structures (WO 2012/121939).